The more than one hundred types of human papillomaviruses (HPV) identified to date (de Villiers et al. (2004) Virology 22, 670-80) are the etiological agents of skin and mucosal papillomas or warts. Persistent infection with high-risk mucosal types, most often HPV16 and HPV18, cause cervical cancer, which constitutes the second leading fatal cancer in women worldwide, causing 274,000 deaths per year. Substantial morbidity results from other non-cervical HPV-related conditions, such as anogenital warts, vulval, vaginal, penile, anal or oropharyngeal cancer.
The development of current prophylactic papillomavirus vaccines was launched by observations that recombinantly expressed major capsid protein L1 self-assembles into virus-like particles (VLP). These empty viral capsids are composed of 360 L1 molecules and resemble native virions in both structure and immunogenicity, yet are non-oncogenic and non-infectious. Moreover, VLP cannot replicate because the cells in which VLP are made contain only L1 and no other papillomavirus genes. Subunit VLP vaccines induce high-titer and type-restricted antibody responses to conformational L1 epitopes (Christensen et al. (1990) J Virol 64, 3151-3156); Kirnbauer et al. (1992) Proc Natl Acad Sci USA 89, 12180-12184; Rose et al. (1994) J Gen Virol 75, 2445-9; Suzich et al. (1995) Proc Natl Acad Sci USA 92, 11553-11557). When applied to women prior to infection, available vaccines targeting the most prevalent high-risk types, HPV16 and HPV18, have demonstrated up to 100% efficacy against persistent infection and associated disease caused by the included types, and thus are potentially able to prevent about 70% of cervical high grade dysplasias and probably cancers. Therefore, use of currently licensed L1 vaccines necessitates continuation of cytological cervical screening of women. The prevention of 96% of cervical cancer would require immunity to 7 high-risk HPV types (16/18/31/33/45/52/58) (Munoz et al. (2004) Int J Cancer 111, 278-85) and the development of more highly multivalent (and presumably costly) L1 VLP vaccines.
The search for alternative broader-spectrum immunogens drew attention to the minor capsid protein L2, which is immunogenically subdominant in the context of co-expressed L1 plus L2 capsids (Roden et al. (2000) Virology 270, 254-257). Immunization of animals with amino (N)-terminal peptide of L2 demonstrated its ability to elicit low-titer neutralizing antibodies that protect against challenge with cognate papillomavirus (PV) types in vivo (Embers et al. (2002) J Virol 76, 9798-805; Gaukroger et al. (1996) J Gen Virol 77 (Pt 7), 1577-83), cross-neutralize heterologous PV types in vitro (Kawana et al. (1999) J Virol 73, 6188-90; Pastrana et al. (2005a) Virology 337, 365-72; Roden et al. (2000) (supra)), and confer cross-protection in vivo (Gambhira et al. (2007a) J Virol 81, 11585-92).
There is a need to develop immunogens or vaccinogens that exhibit high titer neutralizing antibodies against a broad spectrum of HPV types.